title: The serine-threonine kinase LKB1 is essential for survival under energetic stress in zebrafish.
abstract: Mutations in the serine-threonine kinase (LKB1) lead to a gastrointestinal hamartomatous polyposis disorder with increased predisposition to cancer (Peutz-Jeghers syndrome). LKB1 has many targets, including the AMP-activated protein kinase (AMPK) that is phosphorylated under low-energy conditions. AMPK phosphorylation in turn, affects several processes, including inhibition of the target of rapamycin (TOR) pathway, and leads to proliferation inhibition. To gain insight into how LKB1 mediates its effects during development, we generated zebrafish mutants in the single LKB1 ortholog. We show that in zebrafish lkb1 is dispensable for embryonic survival but becomes essential under conditions of energetic stress. After yolk absorption, lkb1 mutants rapidly exhaust their energy resources and die prematurely from starvation. Notably, intestinal epithelial cells were polarized properly in the lkb1 mutants. We show that attenuation of metabolic rate in lkb1 mutants, either by application of the TOR inhibitor rapamycin or by crossing with von Hippel-Lindau (vhl) mutant fish (in which constitutive hypoxia signaling results in reduced metabolic rate), suppresses key aspects of the lkb1 phenotype. Thus, we demonstrate a critical role for LKB1 in regulating energy homeostasis at the whole-organism level in a vertebrate. Zebrafish models of Lkb1 inactivation could provide a platform for chemical genetic screens to identify compounds that target accelerated metabolism, a key feature of tumor cells.
authors.affiliation: Department of Molecular Genetics, Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands.
authors.forename: Yme U
authors.initials: YU
authors.lastname: van der Velden
authors.forename: Liqin
authors.initials: L
authors.lastname: Wang
authors.forename: John
authors.initials: J
authors.lastname: Zevenhoven
authors.forename: Ellen
authors.initials: E
authors.lastname: van Rooijen
authors.forename: Maarten
authors.initials: M
authors.lastname: van Lohuizen
authors.forename: Rachel H
authors.initials: RH
authors.lastname: Giles
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
authors.forename: Anna-Pavlina G
authors.initials: AP
authors.lastname: Haramis
mesh_terms: D000818:Animals; D001481:Basal Metabolism; D016764:Cell Polarity; D004625:Embryo, Nonmammalian / Q000201:enzymology / Q000473:pathology; D004734:Energy Metabolism; D005508:Food Deprivation; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007422:Intestines / Q000473:pathology; D007814:Larva / Q000166:cytology / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D013312:Stress, Physiological; D016019:Survival Analysis; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D029961:Zebrafish Proteins